The use of macrolides for various infectious diseases is well known. Erythromycin was the first compound of this class to be introduced into clinical practice. Since then, additional macrolides, including ketolides have garnered much attention for their ability to treat a wide range of disease states. In particular, macrolides are an important component of therapies for treating bacterial, protozoal, and viral infections. In addition, macrolides are often used in patients allergic to penicillins.
Illustrative of their wide ranging uses, macrolide compounds have been found to be effective for the treatment and prevention of infections caused by a broad spectrum of bacterial and protozoal pathogens. They are also useful for treating respiratory tract infections and soft tissue infections. Macrolide antibiotics are found to be effective on beta-hemolytic streptococci, pneumococci, staphylococci, and enterococci. They are also found to be effective against mycoplasma, mycobacteria, some rickettsia, and chlamydia. 
Macrolide compounds are characterized by the presence of a large lactone ring, which is generally a 14, 15, or 16-membered macrocyclic lactone, to which one or more saccharides, including deoxy sugars such as cladinose and desosamine, may be attached. For example, erythromycin is a 14-membered macrolide that includes two sugar moieties. Spiramycin belongs to a second generation of macrolide compounds that include a 16-membered ring. Third generation macrolide compounds include for example semi-synthetic derivatives of erythromycin A, such as azithromycin and clarithromycin. Finally, ketolides represent a newer class of macrolide antibiotics that have received much attention recently due to their acid stability, and most importantly due to their excellent activity against organisms that are resistant to other macrolides. Like erythromycins, ketolides are 14-membered ring macrolide derivatives characterized by a keto group at the C-3 position (Curr. Med. Chem., “Anti-Infective Agents,” 1:15-34 (2002)). Ketolide compounds are also currently under clinical investigation.
Liang et al. in U.S. Patent Appl. Pub. No. 2006/0100164, the disclosure of which is incorporated herein by reference, describes a new series of triazole-containing ketolide compounds, and an illustrative synthesis thereof. These new compounds show excellent activity against pathogenic organisms, including those that have already exhibited resistance to current therapies. However, it has been discovered herein that side-reactions occur in the processes disclosed by Liang et al leading to impurities that are difficult to remove, and low yields. In addition, starting material impurities are also difficult to remove. Those side-reactions decrease the overall yield of the desired compounds, and those side-products and impurities may complicate the purification of the desired compounds. The occurrence of such side reactions and the presence of such impurities are exacerbated on large commercial scales. In addition, the processes disclosed by Liang et al. include an azide intermediate, which at larger commercial manufacturing scales, may be undesirable, or represent a safety issue. Due to the importance of these triazole-containing ketolide compounds for use in providing beneficial therapies for the treatment of pathogenic organisms, alternative and/or improved processes for their preparation are needed.
The azide intermediate may be avoided by a process that incorporates the side chain intact. However, it has also been reported that introduction of an intact side chain is not a viable process (see, Lee et al., “Process Development of a Novel Azetidinyl Ketolide Antibiotic” Org. Process Res Dev 16:788-797 (2012)). In particular, it has been reported that introduction of an intact side chain leads to an isomeric mixture of products. In addition, it has been reported that introduction of the intact side chain provides only a low yield (<20%).
It has been unexpectedly discovered herein that triazole-containing side chains do not result in an isomeric mixture of products. It has also been unexpectedly discovered herein that triazole-containing side chains provide high yielding reactions. It has also been unexpectedly discovered herein that if the side chain is introduced before the removal of the cladinose, then a single isomer is obtained. It has also been unexpectedly discovered herein that if the side chain is introduced before the removal of the cladinose, then the process provides a high yield.
Described herein are new processes that may be advantageous in preparing compounds of formula (I) that avoid such side-products, and/or may be purified to higher levels of purity. In addition, the processes described herein avoid the azide intermediate by proceeding through a convergent synthetic route.
In one illustrative embodiment of the invention, processes and intermediates are described for preparing compounds of formula (I):
and pharmaceutically acceptable salts, solvates, and hydrates thereof; wherein
R1 is a desosamine or a desosamine derivative;
A is —CH2—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—, —C(O)NHS(O)2—;
B is —(CH2)n— where n is an integer ranging from 0-10; or B is saturated C2-C10; or B is unsaturated C2-C10, which may contain one or more alkenyl or alkynyl groups; or -A-B- taken together is alkylene, cycloalkylene, or arylene;
C represents 1 or 2 substituents independently selected in each instance from hydrogen, halogen, hydroxy, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, and alkyl, alkoxy, heteroalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted; and
W is hydrogen, F, Cl, Br, I, or OH.
In another illustrative embodiment, processes and intermediates are described herein for preparing 11-N-[[4-(3-aminophenyl)-1,2,3-triazol-1-yl]-butyl]-5-desosaminyl-2-fluoro-3-oxoerythronolide A, 11,12-cyclic carbamate, also known as OP-1068, CEM-101, and solithromycin.
In another embodiment of the compounds of formula (I), R1 is a desosamine that includes an optionally protected 2′-hydroxy group. In another embodiment, R1 is a desosamine that includes a protected 2′-hydroxy group. In another embodiment, the protecting group is an acyl group. In another embodiment, the protecting group is a sterically hindered acyl group, such as a branched alkyl, aryl, heteroaryl, arylalkyl, arylalkyl, or heteroarylalkyl acyl group, each of which is optionally substituted. In another embodiment, the protecting group is an optionally substituted benzoyl group. In another embodiment, the protecting group is a benzoyl group. In another embodiment, -A-B- is alkylene, cycloalkylene, or arylene. In another embodiment, -A-B- is alkylene. In another embodiment, -A-B- is C3-C5 alkylene. In another embodiment, -A-B- is C4 alkylene. In another embodiment, -A-B- is —(CH2)4—. In another embodiment, C is optionally substituted aryl, heteroaryl, arylalkyl, or heteroarylalkyl. In another embodiment, C is optionally substituted aryl or heteroarylalkyl. In another embodiment, C is optionally substituted aryl. In another embodiment, C is substituted aryl. In another embodiment, C is amino substituted aryl. In another embodiment, C is amino substituted phenyl. In another embodiment, C is 3-aminophenyl. In another embodiment, W is H or F. In another embodiment, W is F.
It is to be understood that each and every combination, and each and every selection, and combination thereof, of the forgoing and following embodiments is described herein. For example, in another embodiment, R1 is a desosamine that includes a protected 2′-hydroxy group, where the protecting group is an acyl group; or R1 is a desosamine that includes a protected 2′-hydroxy group, where the protecting group is a sterically hindered acyl group; or R1 is a desosamine that includes a protected 2′-hydroxy group, where the protecting group is a benzoyl group, and -A-B- is C3-C5 alkylene; or R1 is a desosamine that includes a protected 2′-hydroxy group, where the protecting group is a benzoyl group, and -A-B- is —(CH2)4—; or R1 is a desosamine that includes a protected 2′-hydroxy group, where the protecting group is a benzoyl group, and -A-B- is —(CH2)4—, and C is optionally substituted aryl; or R1 is a desosamine that includes a protected 2′-hydroxy group, where the protecting group is a benzoyl group, and -A-B- is —(CH2)4—, and C is 3-aminophenyl; and so forth.
It is to be understood that the processes described herein may be advantageously performed simply and cost-effectively. It is further to be understood that the processes described herein may be scaled to large production batches. It is further to be understood that the processes described herein are performed in fewer steps than conventional processes. It is further to be understood that the processes described herein are performed are more convergent, and/or require shorter linear sub-processes, than conventional processes. It is further to be understood that the processes described herein may concomitantly produce fewer or different side products than known processes. It is further to be understood that the processes described herein may yield compounds described herein in higher purity than known processes.